Carcinoembryonic antigen (CEA) is the most widely used serum marker for colorectal cancer. A knowledge of the factors that influence its level in the circulation is necessary for accurate interpretation of levels in patients. We have described a system that clears CEA from the blood in rats and have now shown that the system also operates in humans. The first stage in clearance is endocytosis by a receptor on the liver macrophage (Kupffer cell). We have also shown that a glycoprotein related to but not identical with alpha1-acid glycoprotein can bind to CEA and prevent binding to the Kupffer cell receptor. We will examine the properties of CEA receptor binding in detail including studies of its biosynthesis using pulse chase experiments. We intend to determine the structure of the receptor from human liver by sequencing peptides produced from the purified protein and to use these sequences to construct oligonucleotide probes for cloning its gene. The structure will be compared to structures of known receptors and to the structure of the alpha1-acid like glycoprotein. Because CEA is related to the immunoglobulin supergene family, we will determine if this receptor is involved in endocytosis of other members of the family and if there is a common signal sequence on these proteins that destine them for clearance by the liver. The second stage of CEA clearance is transfer of the modified CEA to the hepatocyte for final degradation. This transfer involves endocytosis of modified CEA by the asialoglycoprotein receptor. We will study this system using both isolated Kupffer cells and hepatocytes from rats and humans to determine if this mechanism of transfer applies to other glycoproteins and if this represents a major physiological role for the asialoglycoprotein receptor.